Lim Jung Yeon, Reighard Charles P, Crowther Damian C
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK.
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK and.
Hum Mol Genet. 2015 Jul 15;24(14):3929-38. doi: 10.1093/hmg/ddv130. Epub 2015 May 7.
Brain-derived neurotrophic factor (BDNF) has a crucial role in learning and memory by promoting neuronal survival and modulating synaptic connectivity. BDNF levels are lower in the brains of individuals with Alzheimer's disease (AD), suggesting a pathogenic involvement. The Drosophila orthologue of BDNF is the highly conserved Neurotrophin 1 (DNT1). BDNF and DNT1 have the same overall protein structure and can be cleaved, resulting in the conversion of a full-length polypeptide into separate pro- and mature-domains. While the BDNF mature-domain is neuroprotective, the role of the pro-domain is less clear. In flies and mammalian cells, we have identified a synergistic toxic interaction between the amyloid-β peptide (Aβ1-42) and the pro-domains of both DNT1 and BDNF. Specifically, we show that DNT1 pro-domain acquires a neurotoxic activity in the presence of Aβ1-42. In contrast, DNT1 mature-domain is protective against Aβ1-42 toxicity. Likewise, in SH-SY5Y cell culture, BDNF pro-domain is toxic only in the presence of Aβ1-42. Western blots indicate that this synergistic interaction likely results from the Aβ1-42-induced upregulation of the BDNF pro-domain receptor p75(NTR). The clinical relevance of these findings is underlined by a greater than thirty fold increase in the ratio of BDNF pro- to mature-domains in the brains of individuals with AD. This unbalanced BDNF pro:mature-domain ratio in patients represents a possible biomarker of AD and may offer a target for therapeutic intervention.
脑源性神经营养因子（BDNF）通过促进神经元存活和调节突触连接，在学习和记忆中发挥关键作用。阿尔茨海默病（AD）患者大脑中的BDNF水平较低，提示其与发病机制有关。BDNF在果蝇中的同源物是高度保守的神经营养因子1（DNT1）。BDNF和DNT1具有相同的整体蛋白质结构，并且可以被切割，导致全长多肽转化为单独的前体结构域和成熟结构域。虽然BDNF成熟结构域具有神经保护作用，但其前体结构域的作用尚不清楚。在果蝇和哺乳动物细胞中，我们发现淀粉样β肽（Aβ1-42）与DNT1和BDNF的前体结构域之间存在协同毒性相互作用。具体而言，我们发现DNT1前体结构域在Aβ1-42存在的情况下获得了神经毒性活性。相比之下，DNT1成熟结构域对Aβ1-42毒性具有保护作用。同样，在SH-SY5Y细胞培养中，BDNF前体结构域仅在Aβ1-42存在时具有毒性。蛋白质免疫印迹表明，这种协同相互作用可能是由Aβ1-42诱导的BDNF前体结构域受体p75（NTR）上调所致。AD患者大脑中BDNF前体结构域与成熟结构域的比例增加了三十多倍，突出了这些发现的临床相关性。患者中这种不平衡的BDNF前体结构域：成熟结构域比例可能是AD的一种生物标志物，并可能为治疗干预提供靶点。
